3-aminoindazoles

ABSTRACT

NEW 1-ARYL-3-AMINOINDAZOLES, E.G., THOSE OF THE FORMULA

United States Patent Gschwend 1 Aug. 1, 1972 [54] S-AMINOINDAZOLES3,301,482 3/ l970 Levon et al. ..260/3l0 C 7 I t Heinz Werner GschwendMillb rn, l 2] men or NJ u Pnmary Examiner-Henry R. .hles

Assistant Examiner-Robert T. Bond Asslgneei Clba'GelgY Corpomuon,Ardsley, Attorney-Harry Goldsmith, Bryant W. Brennan,

Joseph G. Kolodny and Edward J. Sites [22] Filed: Feb. 7, 1969 ABSTRACT[21] Appl. No.: 797,702

New l-aryl-3-am1nomdazoles, e.g., those of the formula [52] US.Cl......260/310 C, 260/247.5 B, 260/295 B,

260/268 BC, 260/296 B, 260/293.7, 8 424/273, 424/267, 424/250, 424/248,&

424/263 N [51] Int. Cl. ..C07d 49/02 [58] Field ofSearch ..260/3l0 C, I

' 295 P1296 B, 293 JPIA EL LQ l mwwm R =Ar0matic radical R =H, alkyl,free, esterified 0r etherified hydroxyalkyl R =Aza-(alkyl,cycloalkyl-alkyl, aralkyl, alkanoyl, cycloalkyl-alkanoyl or aralkanoyl)[56] References Clted R +R =Aza-(alkylene, free, esterified oretherified hydroxy-alkylene 0r aralkylene) UNITED STATES PATENTS i dl$VP EEEQQBFE. PPl$1?PE @Rl$'or 3,133,081 5/1964 Lafferty et al..260/3l0 C l 4 Claims, N0 Drawings 3-AM1N0lNDAZOLFS SUMMARY OF THEINVENTION The present invention concerns and has for its object theprovision of new l-aryl-3-aminoindazoles, more particularly of those ofFormula I PA R2 in which Ph is a 1,2-phenylene radical, R is an aromaticradical, R is hydrogen, lower alkyl or free, esterified or etherifiedhydroxyalkyl, R is an aza- (lower alkyl, cycloalkyl-alkyl, aralkyl,alkanoyl, cycloalkyl-alkanoyl or aralkanoyl) group or R and R when takentogether, represent aza-(alkylene, free, esterified or etherifiedhydroxyalkylene or aralkylene), in which R2I IR the heteroatoms areseparated by at least two carbon atoms, of acyl derivatives, quatemariesand salts thereof, as well as of corresponding pharmaceuticalcompositions and of methods for the preparation and application of theseproducts. Said compositions are useful antidepressants andantiinflammatory agents.

DESCRIPTION OF THE PREFERRED EMBODIMENTS The l,2-pheny1ene radical Phand the isoor heterocyclic aryl radical R are unsubstituted orsubstituted by one or more than one, preferably by l or 2, of the sameor of different substituents, for example, by lower alkyl, such asmethyl, ethyl, n-or i-propyl or -butyl, free, etherified or esterifiedhydroxy or mercapto groups, such as lower alkoxy or alkylmercapto, e.g.,methoxy, ethoxy, nor i-propoxy or -butoxy, halogeno, e.g., fluoro,chloro or bromo, trifluoromethyl, nitro or amino, especially di-loweralkylamino, e.g., dimethylamino or diethylarnino. Preferred1,2-phenylene radicals Ph are l,2-phenylene, (lower alkyl)-l,2-phenylene, (lower alkoxy)-l,2-phenylene, (loweralkylmercapto)-1,2-pheny1ene, (halogeno)-l ,2-phenylene,(trifluoromethyD- l ,2-phenylene, (mtro)- l ,2 phenylene or (di-loweralkylamino)-l,2-phenylene, and the aromatic radical R is preferablymonocyclic and represents, for example, I-lPh, especially phenyl, (loweralkyl)-phenyl, (lower alkoxy)-phenyl, (lower alkylmercapto)-phenyl,(halogeno)-phenyl, (trifluoromethyl)-phenyl, (nitro)-phenyl or (di-loweralkylamino)-phenyl, as well as pyridyl or (lower alkyl)- pyridyl. Theterm lower referred to above and hereinafter in connection with organicradicals or compounds respectively, defines such with up to seven,preferably up to four, carbon atoms.

A lower alkyl group R is, for example, such mentioned above, but alsonor i-pentyl, n-hexyl or n-heptyl. A lower hydroxyalkyl radical R is anyof the abovementioned alkyl radicals containing in any position of thechain, which is separated from the adjacent nitrogen atom by at leasttwo carbon atoms, one

hydroxy group. The latter may be esterified, e.g., by a lower alkanoicacid, e.g., acetic, propionic, butyric or pivalic acid, or etherified,e.g., by an alcohol, such as a lower alkanol.

An aza-(lower alkyl, cycloalkyl-alkyl or aralkyl) radical R is, forexample, amino-lower alkyl, monoor di-lower alkylamino-lower alkyl,lower alkyleneiminolower alkyl, monoaza-lower alkyleneimino-lower alkyl,3 to 7 ring-membered cycloalkylamino-lower alkyl, cycloalkyl-loweralkylamino-lower alkyl, N-cycloalkyl- N-lower alkylamino-lower alkyl orN-cycloalkyl-lower alkyl-N-lower alkylamino-lower alkyl, l-IPh-loweralkylamino-lower alkyl or N-lower alkyl-N-, I-IPh-lower alkylamino-loweralkyl, e.g., w(amino, methylamino, ethylarnino, nor i-propylamino orn-butylamino; dimethylamino, Nmethyl-N-ethylamino, diethylamino,di-n-propylamino, di-isopropylamino or di-n-butylarnino, ethyleneimino,pyrrolidino, Z-methylpyrrolidino, piperidino, 2- or 4-methyl-piperidino,1,6- or 2,5-hexamethyleneimin0, 1 ,7- or 2,6-heptamethyleneimino,piperazino, 4-methyl or ethylpiperazino, cyclopropylarnino,cyclopentylarnino, cyclohexylamino, cyclopropylmethylamino, 2-cyclopentylethylarnino, N-cyclopentyl-N- methylamino,N-cyclohexyl-N-methylamino, N- cyclohexyl-N-ethylamino,N-cyclopentylmethyl-N- ethylamino, benzylamino, 1- or Z-phenethylarnino,N- methyl-N-benzylamino or N-ethyl-N-benzylamino)- ethyl, -propyl,-butyl or -pentyl. The aza-(lower alkanoyl, cycloalkylalkanoyl oraralkanoyl) radicals R are, for example, the above-substituted alkylradicals, in which the carbon atom, attached to the 3-amino nitrogenatom, is substituted by an oxo group.

R and R when taken together, preferably represent monoaza-lower alkyleneor N-(hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl, loweralkoxy-lower alkyl, HPh-lower alkyl or HPh)-monoaza-lower alkylene,e.g., 3-aza-l,5-pentylene, 3-aza-l,5or 1,6-hexylene, 4- aza-l,7or2,6-heptylene or 3-(methyl, ethyl, n-propyl, 2-hydroxyethyl,3-hydroxypropyl, 2-acetoxyethyl, 2- methoxyethyl, 4-methoxybutyl,benzyl, Z-phenethyl, phenyl or 4-tolyl)-l,5pentylene. In the above aminogroups two hetero atoms are separated by at least two carbon atoms.

Acyl derivatives of the compounds of Formula I in which R is hydrogenand R is aza-(alkyl, cycloalkylalkyl or aralkyl), are preferably thosederived from lower alkanoic or HPh-lower alkanoic acids, such as theacetyl, propionyl, butyryl, pivalyl, benzoyl or phenylacetylderivatives. Quatemaries are preferably lower alkylor HPh-loweralkylammonium salts, such as halides, sulfates or sulfonates, e.g.,methyl-, ethylor benzylammonium chlorides, bromides, iodides, methylorethylsulfates, methane, ethane or p-toluene sulfonates.

The compounds of the invention exhibit valuable pharmacologicalproperties. Apart from antiinflammatory activity, they exhibit primarilyantidepressant effects, as can be demonstrated in animal tests, usingadvantageously mammals, e.g., mice or rats, as test objects. They can beapplied enterally or parenterally, e. g., in the form of aqueoussolutions or suspensions, in the dosage range between about 0.1 and 50mg/kg/day, preferably between about 0.5 and 25 mg/kg/day, advantageouslybetween about 1 and 10 mg/kg/day. The

antiinflammatory effects can be determined, for example, in the rat pawedema test system [Winter et al., Proc. Soc. Exp. Biol. & Med. III, 544(1962)] and the anti-depressant effects, for example, in the amphetaminepotentiation test system (P. Carlton, Psychopharmacologia 1961, Vol. II,364). In the latter, about 8 month old male rats are trained to press abar every 30 seconds, in order to avoid an electric shock appliedthrough the floor grid. In case the animals receive intraperitoneally0.25 mg/kg/day of amphetamine, their performing rate for avoiding saidshocks during a period of about 26% hours is higher than that of placebotreated animals. In case said animals receive the compounds of theinvention orally or intraperitoneally in the above dosages and about 45minutes later the amphetamine, their rate of avoidance is highest, ascompared with that of animals receiving (a) saline alone, (b) saline andamphetamine, or (c) saline and the compounds of the invention.Accordingly, the compounds of this invention are useful antidepressants,e.g., such of the imipramine-type, as well as useful intermediates inthe manufacture of other valuable, e.g., pharmacologically active,products.

Particularly useful are the compounds of Formula I, in which Ph isl,2-phenylene, (lower a1kyl)-l,2-phenylene, (loweralkoxy)-l,2-phenylene, (lower alkylmercapto)- l ,Z-phenylene,(halogeno)-l ,2-phenylene, (trifluoromethyl l ,Z-phenylene, (nitro)- 1,2-phenylene or (di-lower alkylamino)-l,2-phenylene, R is phenyl, (loweralkyl)-phenyl, (lower alkoxy)-phenyl, (lower alkylmercapto)-phenyl,(halogeno)-phenyl, (trifluoromethyl)-phenyl, (nitro)-phenyl, (di-lowera1- kylamino)-phenyl, pyridyl or (lower a1kyl)-pyridyl, R is hydrogen,lower alkyl, hydroxy-lower alkyl, lower alkanoyloxy-lower alkyl or loweralkoxy-lower alkyl, R is (amino, monoor di-lower alkylamino, loweralkyleneimino, monoaza-lower alkyleneimino, 3 to 7 ring-memberedcycloalkylamino, cycloalkyl-lower alkylamino, N-cycloalkyl-N-loweralkylamino, N- cycloalkyl-lower alkyl-N-lower alkylamino, HPh-loweralkylamino or N-lower alkyl-N-HPh-lower alkylamino)-lower alkyl or-alkanoyl, or R and R when taken together, represent monoaza-loweralkylene or N-(hydroxy-lower alkyl, lower alkanoyloxy-lower a1- kyl,lower alkoxy-lower alkyl, HPh-lower alkyl or HPh)-monoaza-loweralkylene, in which R2-1 l-R the hetero atoms are separated by at leasttwo carbon atoms, the lower alkanoyl or l-IPh-lower alkanoyl derivativesof the compounds in which R is hydrogen and R is aza-(alkyl,cycloalkylalkyl or aralkyD-lower alkyl, lower alkyl or HPh-alkylquateman'es or acid addition salts thereof.

Preferred are the compounds of Formula II N-C-alk-Am II piperazino,4-methylpiperazino or 4-ethylpiperazino,

alk is methylene, l,lor 1,2-ethylene, Z is 0x0 or 2 hydrogens and R ishydrogen, or therapeutically useful acid addition salts thereof, aboveall the l-(4- fluorophenyl )-3-( Z-dimethylaminoethylamino )-indazoleand said salts, which show anti-depressant activity, for example, at ani.p. dose of about 6 mg/kg/day in the rat's amphetamine potentiationtest.

The compounds of the invention are prepared according to methods inthemselves known. Advantageously they are obtained by converting in acompound of the formula in which X is a substituent capable of beingconverted into X into said amino group and, if desired, converting anyresulting compound into another compound of the invention.

A substituent X capable of being converted into is, for example, the

i :1? T E.

group. The corresponding starting material, or an alkali metal saltthereof, is reacted with a reactive derivative of the alcohol, oradvantageously the acid R's-OH, preferably a halideIeIgi, chloride orbromide, sulfate or sulfonate, e.g., methane, ethane, benzene orp-toluene sulfonate, or anhydride respectively.

Another substituent X is, for example, the

l Br -Y group wherein Y is a substituent capable of being converted intoR e.g., (a) reactively esterified hydroxyalkyl or -alkanoyl, e.g., saidhalogenoor sulfonyloxyalkyl or -alkanoyl, or (b) a (nitro, oximino,imino, cyano, carbamoyl, isocyanato or esten'fied carboxyamino, e.g.,carbalkoxyamino)-alkyl, -aklenyl.

use of reducing agents, such as simple or complex light methyl hydrides,advantageously boron hydrides r alkali metal aluminum hydrides, e.g.,lithium aluminum hydride. lsocyanates and urethanes may also besubjected to hydrolysis, e.g., with the use of aqueous mineral acids oralkalies.

The compounds of the invention so obtained may be converted into eachother according to known methods. For example, resulting compoundscontaining a primary or secondary amino groups, may be reacted with areactive ester of a corresponding alcohol, e.g., alkanol or alkanediol,or may be acylated, for example, with a reactive functional derivativeof a corresponding acid, such as a halide or anhydride thereof, orresulting acyl derivatives may be hydrolyzed, for example, with the useof acidic or alkaline hydrolyzing agents, or advantageously reduced,e.g., with said simple or complex light metal hydrides. Resultingtertiary amines may be quaternized in the usual manner, for example withthe use of reactive esters of alcohols, preferably of lower alkanols,but also of l-lPh-alkanols, and said hydrohalic, sulfuric or sulfonicacids.

The compounds of the invention are obtained in the free form or in theform of their salts, depending on the conditions under which the processis carried out; the salts are also included in the present invention.Salts that are obtained can be converted into the free bases in knownmanner, for example, with alkalies or ion exchangers. Free bases thatare obtained can be converted into salts by reaction with inorganic ororganic acids, especially those that are suitable for the formation oftherapeutically useful salts. Such acids are, for example, mineralacids, e.g., hydrochloric, hydrobromic, sulfuric, phosphoric, nitric orperchloric acid; aliphatic or aromatic carboxylic or sulfonic acids,e.g., formic, acetic, propionic, succinic, glycollic, lactic, malic,tartaric, citric, ascorbic, maleic, hydroxymaleic, pyroracemic,phenylacetic, benzoic, 4- aminobenzoic, anthranilic, 4-hydroxybenzoic,salicylic, 4-aminosalicyclic, embonic, nicotinic, methanesulfonic,ethanesulfonic, hydroxyethanesulfonic, ethylenesulfonic,benzenesulfonic, p-toluenesulfonic, halogenbenzenesulfonic, sulfanilicand cyclohexylsulfamic acid; methionine, tryptophane, lysine andarginine.

These or other salts of the invention, for example, the picrates, canalso be used for purification of the bases obtained; the bases areconverted into salts, the salts are separated and the bases areliberated from the salts. in view of the close relationship between thefree compounds and the compounds in the form of their salts, whenever afree base is referred to in this context, a corresponding salt is alsointended, provided such is possible or appropriate under thecircumstances.

The above reactions are carried out according to standard methods, inthe presence or absence of diluents, preferably such as are inert to thereagents and are solvents thereof, of catalysts, condensing agentsand/or inert atmospheres, at low temperatures, room temperature oradvantageously elevated temperatures, at atmospheric or superatmosphericpressure.

The invention further includes any variant of the present process, inwhich an intermediate product obtainable at any stage of the process isused as starting material and any remaining steps are carried out, orthe process is discontinued at any stage thereof, or in which thestarting materials are formed under the reaction conditions, or in whichthe reaction components are used in the form of their salts. Forexample, the amines or alcohols mentioned above may be used in the formof their alkali metal, e.g., sodium or potassium salts. Mainly, thosestarting materials should be used in the process of the invention thatlead to the formation of those compounds indicated above as beingspecially al s- The starting material used is known (US. Pat. No.3,133,081) or, if new, may be prepared according to known methods. Forexample, that in which X is primary amino, can be obtained by reacting al-l-Ph-glyoxylic acid derivative, e.g., an ester or the nitrile thereof,with an R -hydrazine, and ring-closing the hydrazone obtained with theaid of lead tetraacetate and boron trifluoride. Any resulting l-R-indazole-3-carboxylic acid derivative, e.g., the ester or nitrile, isthen hydrolyzed to the free acid with aqueous alkalies or acidsrespectively, e.g., sodium hydroxide or sulfuric acid. Said 3-acid isthen subjected to Curtius degradation, i.e., converted into its halidewith the use of thionyl or phosphorus halides, e.g., thionyl chloride orphosphorus oxychloride, the halide reacted with sodium azide, theresulting azide rearranged into the isocyanate or urethane by heating itin the presence or absence of an alcohol, e.g., lower alkanol, andhydrolyzing them to the 3-amines with the use of aqueous alkalies, e.g.,potassium hydroxide. Said amine can then be reacted with a loweralkanoic acid or free or etherified hydroxy-alkanoic acid, and the amideformed reduced with said light metal hydrides, to yield the compounds inwhich X is These can further be reacted either with reactive derivativesof the alcohol or acid Y--Ol-l (analogous to those of the formula &OH)or with ethylene oxide. Any resulting 3-hydroxyalkylamino or-alkanoylamino compound can be reactively esterified, e.g., with thionylor sulfonyl halides, or oxidized to the corresponding aldehydes, ketonesor acids, for example, with hydrogen peroxide, alkali metal chromates orpermanganates, mercuric, manganese or silver oxide in acidic or alkalinemedia. Resulting haloalkyl compounds can be reacted with silver nitriteor alkali metal cyanides, or resulting acids converted into thecorresponding amides or azides as shown above, or the aldehydes orketones reacted with armnonia, amines or hydroxylamine, in order toobtain the nitro compound or nitrile, the Schiffs base, oxirne,isocyanate or urethane starting material.

The compounds of the invention can be used, for example, for themanufacture of pharmaceutical compositions containing them inconjunction or admixture with inorganic or organic, solid or liquidpharmaceutical excipients, suitable for enteral or parenteraladministration. Suitable excipients are substances that do not reactwith the compounds of the invention, for example, water, gelatine,sugars, e.g., lactose, glucose or sucrose, starches, e.g., corn starchor arrowroot, stearic acid or salts thereof, e.g., magnesium or calciumstearate, talc, vegetable fats or oils, gums, alginic acid, benzylalcohols, glycols and other known excipients. The compositions may be,for example, in solid form as tablets, dragees or capsules, or in liquidform as solutions, suspensions or emulsions. They may be sterilizedand/or contain adjuvants, such as preserving, stabilizing, wetting oremulsifying agents, solution promoters, salts for regulating the osmoticpressure and/or buffers. They may further contain other therapeuticallyvaluable substances. Said pharmaceutical compositions are prepared byconventional methods and contain about 0.1 to 75 percent, moreparticularly 1 to 50 percent, of the active ingredient. They are alsoincluded within the scope of the present invention.

The following examples are intended to illustrate the invention and arenot to be construed as being limitations thereon. Temperatures are givenin degrees Centigrade, and all parts wherever given are parts by weight.

EXAMPLE l Through the solution of 6.0 g l-(4-fluorophenyl)-3-bromoacetylarnino-indazole in 250 ml tetrahydrofuran, a slow stream ofdimethylamine is passed while stirring, until saturation has beenreached. The mixture is stirred for 16 hours at room temperature,filtered and the filtrate evaporated in vacuo. The residue is taken upin methylene chloride, the solution washed with aqueous sodiumbicarbonate, dried, filtered and evaporated, to yield thel(4-fluorophenyl)-3- dimethylaminoacetylamino-indazole of the formulamelting at ll1ll.

It is taken up in the minimum amount of ethanol and the solutionneutralized with ethereal hydrogen chloride, to yield the correspondinghydrochloride melting at l73-l 75 The starting material is prepared asfollows: The mixture of 45 g methyl phenylglyoxylate, 45 g 4-tluorophenylhydrazine hydrochloride, 27 g sodium acetate and 1.5 literethanol is refluxed for 24 hours while stirring. It is filtered hot, thefiltrate cooled and the precipitate formed filtered off, to yield themethyl phenylglyoxylate 4-fluoropphenyl-hydrazone, melting at 8890.

The solution of 62 g thereof in 2 liters methylene chloride is addeddropwise to the solution of 1 12 g lead tetraacetate in 1.2 litermethylene chloride while stirring and cooling with ice. The mixture isstirred for 2 hours at room temperature, whereupon 1 liter water isadded while stirring. The mixture is filtered with the aid of infusorialearth, the filtrate washed with water and aqueous sodium bicarbonate,dried and concentrated to about 800 ml. To the concentrate, 280 mlborontrifluoride-etherate are added, and the mixture refluxed for 5-%hours. After cooling, water is added dropwise, the organic layerseparated, washed with aqueous sodium bicarbonate, dried and evaporated.The residue is recrystallized from ethanol, to yield thel-(4-fluorophenyl)-indazole-3-carboxylic acid methyl ester melting atl27l 29 The mixture of 51.5 g thereof, 350 ml ethanol, 350 ml water and190 ml N aqueous sodium hydroxide is stirred at for 3 hours and stirredovernight at room temperature. It is concentrated in vacuo, theconcentrate acidified with 195 ml N hydrochloric acid and 1 liter wateris added. The precipitate formed is filtered off and dried in vacuo, toyield the corresponding acid melting at l 8919 1 The mixture of 10.2 gthereof and 50 ml thionyl chloride is refluxed for l-% hours andevaporated in vacuo. The residue is taken up in 350 ml acetone and thesolution of 17.5 g sodium azide in 70 ml water is added while stirringvigorously. Stirring is continued for 2 hours at room temperature, andthe mixture poured onto 250 ml ice and water. The precipitate formed isfiltered off and dried in vacuo overnight at room temperature, to yieldthe l-(4-fluorophenyl)-indazole-3-carboxylic acid azide.

The suspension of 10.9 g thereof in 300 ml ethanol is refluxed overnightwhile stirring under nitrogen, during which time it becomes homogeneous.It is concentrated in vacuo to about ml and the concentrate cooled in anice bath. The precipitate formed is filtered off, to yield thel-(4-fluorophenyl)-3-carbethoxyamino-indazole melting at l20l 22 To thesolution of 6.0 g thereof in 50 ml hot ethanol, 50 ml 30 percent aqueouspotassium hydroxide are added and the whole is refluxed for 16 hours. Itis concentrated in vacuo, the concentrate extracted with methylenechloride, the extract dried, filtered, evaporated and the residuerecrystallized from diethyl ether, to yield thel-(4-fluorophenyl)-3-aminoindazole melting at l29-l 3 1 To the mixtureof 8.2 g thereof, 250 ml methylene chloride and 4.5 g anhydrous sodiumbicarbonate, 4.5 ml bromoacetyl bromide are added while stirring, andstirring is continued for 17 hours. It is thoroughly washed with water,dried, filtered and evaporated, to yield the l-(4-fluorophenyl)-3-bromoacetylarninoindazole melting at 19ll93 EXAMPLE 2The solution of 5.4 g l-(4-fluorophenyl)-3- dimethylaminoacetylamino-indazole in 35 ml tetrahydrofuran is added dropwise to 37 ofa 1 molar solution of borane in tetrahydrofuran while stirring at 0under nitrogen, and stirring is continued for 20 minutes at thistemperature. Hereupon the mixture is refluxed for 2 hours, cooled andcarefully combined with 23 ml 5N hydrochloric acid. It is concentratedunder normal pressure, the concentrate made basic with saturated aqueoussodium carbonate and extracted with methylene chloride. The extract isdried, filtered and evaporated in vacuo, 5.4 g of the residue are takenup in 35 ml acetone, one equivalent of ethereal hydrogen chloride isadded and the precipitate formed filtered off, to yield thel-(4-fluorophenyl)-3- (2-dimethylaminoethylamino)-indazole hydrochlorideof the formula -HCl melting at 125l 27.

EXAMPLE 3 melting at 253255.

EXAMPLE 4 In the exactly analogous manner shown in the previousexamples, one obtains the following compounds of Formula II, R H fromequivalent amounts of the corresponding starting material:

R alk Am Salt m.p.

phenyl CH piper- 8082 idino decomp.

H CH, NH 23 l-23 3 1,2-CJL, N(CH 166-168 piper- 200-202 idino CH,maleate 55 decomp. N(C,H HC] 178-] 4-chloro- 0 N(CH l27l29 phenyl 0piper- 134-136" idino 0 l,l-C H N(CH;,) lO9-lll" H, 2 NHCl-l HCl 1 77N(CH;,) l76l78 n u u N(C2H5)2 u piper- 224226 idino The correspondingl-R -3-amino-indazoles have the following characteristics:

R phenyl m.p. 85-87 R =4-chlorophenyl m.p. l 3914l.

EXAMPLE 5 Preparation of 10,000 tablets each containing 50.0 mg of theactive ingredient:

Fonnula: l-(4-fluorophenyl)-3-(2- dimethylamino-ethylamino)-indazolehydrochloride 500.00 3 Lactose 1,706.00 g Corn starch 90.00 gPolyethylene glycol 6,000 90.00 g Talcum powder 90.00 g Magnesiumstearate 24.00 g Purified water q.s.

PROCEDURE All the powders are passed through a screen with openings of0.6 mm. Then the drug substance, lactose, talcum, magnesium stearate andhalf of the starch are mixed in a suitable mixer. The other half of thestarch is suspended in 45 ml water and the suspension added to theboiling solution of the polyethylene glycol in 180 ml water. The pasteformed is added to the powders which are granulated, if necessary, withan additional amount of water. The granulate is dried overnight at 35,broken on a screen with 1.2 mm openings and compressed into tabletsusing concave punches with 7.1 mm diameter, uppers bisected.

In the analogous manner tablets are prepared, comprising anothercompound of the previous examples, e.g., thel-(4-chlorophenyl)-3-piperazinoacetylaminoindazole dihydrochloride, asthe active ingredient.

lclaim:

1. A compound having the formula wherein R is phenyl, (loweralkyl)-phenyl, (lower alkoxy)-phenyl, (halogeno)-phenyl or(trifluoromethyl)- phenyl, R is hydrogen or lower alkyl, Am is monoordi-lower alkylamino, 5 to 7 ring-membered lower alkylene imino,piperazino, 4-methyl or ethyl-piperazino, alk is lower alkylene, inwhich groups lower defines such with up to four carbon atoms, Z is 0x0or two I 1 12 hydrogen atoms and R is hydrogen or halogeno, or acidaddition salts thereof; therapeutically useful acid addition saltsthereof. 3. A compound as claimed in claim 1 and being the 2. A compoundas claimed in claim 1, in which for-1-(4-fluorophenyl)-3-(2-dimethylaminoethylamino)- mula R. is phenyl,4-(fluoro or chloro)-phenyl, R is indazole or therapeutically usefulacid addition salts hydrogen and Am is methylamino, ethylamino, 5thereof. l dimethylarnino, diethylamino, pyrrolidino, piperidino, A p unas fllm qln Claim 1 and heing the piperazino, 4-methylpiperazino or4-ethy1piperazino, pf y -P P f Y 1 is methylene, 1 1 or 1 2- h 1 Z is0x0 or 2 or therapeutically useful acid addition salts thereof.

hydrogens and R is hydrogen, or therapeutically useful 10

2. A compound as claimed in claim 1, in which formula R4 is phenyl,4-(fluoro or chloro)-phenyl, R5 is hydrogen and Am is methylamino,ethylamino, dimethylamino, diethylamino, pyrrolidino, piperidino,piperazino, 4-methylpiperazino or 4-ethylpiperazino, alk is methylene,1,1- or 1,2-ethylene, Z is oxo or 2 hydrogens and R6 is hydrogen, ortherapeutically useful acid addition salts thereof.
 3. A compound asclaimed in claim 1 aNd being the1-(4-fluorophenyl)-3-(2-dimethylaminoethylamino)-indazole ortherapeutically useful acid addition salts thereof.
 4. A compound asclaimed in claim 1 and being the1-(4-chlorophenyl)-3-piperazinoacetylamino-indazole or therapeuticallyuseful acid addition salts thereof.